The compounds capsinoids include capsiate, dihydrocapsiate and nordihydrocapsiate. Especially, capsiate, which is mainly found in a nonpungent cultivar of red pepper, CH19 sweet, is known to provide effects comparable to those of capsaicin, including activation of the capsaicin receptor, suppression of body fat accumulation, and the like. Because capsiate is nonpungent, various researches are carried out on its mechanism. However, no concrete achievements have been made as yet.
Inflammatory response refers to the complex physiological response of vascular tissues to harmful stimuli, such as damages, bacteria, fungi, viruses, etc., including enzymatic activation caused by various inflammatory mediators and immunocytes, secretion of inflammatory mediators, infiltration of body fluid, cell migration, tissue destruction, or the like. As a result, such symptoms as erythema, edema, fever and pain are accompanied. Inflammatory response is a protective attempt by the organism to remove exogenous source of infection, regenerate damaged tissues and restore biological functions. However, excessive or prolonged inflammatory response, which may be caused by unremoved antigens or internal substances, can lead to damaged mucosa, tissue destruction, or such diseases as cancer, inflammatory skin disease, inflammatory bowel disease, arthritis, etc.
Until now, antihistaminic agents, vitamin ointments, and adrenocorticotropic hormones have been commonly used to treat inflammatory diseases. However, these drugs provide temporary effect only and sometimes are associated with severe side reactions. Accordingly, there is a need for the development of new substances effective in treating inflammatory diseases without side effects.
Angiogenesis is a process involving the growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal process in embryonic development, as well as in wound healing and periodical changes in women's genital organs. However, uncontrolled angiogenesis may lead to pathological growth. Angiogenesis-related diseases include angioma, angiofibroma, vascular malformation and cardiovascular diseases such as arteriosclerosis, vascular adhesion, sclerotic edema and diabetes. Angiogenesis-related ophthalmologic diseases include corneal angiogenesis, neovascular glaucoma, diabetic retinopathy, angiogenesis-induced corneal disease, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, trachoma, and the like. And angiogenesis-related diseases include chronic inflammatory diseases such as rheumatoid arthritis, eczematous diseases, telangiectasis, pyogenic granuloma, seborrheic dermatitis, psoriasis, contact dermatitis, atopic dermatitis and so on, and skin diseases such as acne. Angiogenesis is also a fundamental step in the growth and transition of tumors [Ophthalmol. 102, 1261-1262, 1995; J. Am. Acad. Derm. 34(3):486-497, 1996; Circulation 93(4):632-682, 1996; Cell 86: 353-364, 1996].
The process of angiogenesis is composed of the steps: promotion of the growth of endothelial cells by tumor cytokine, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF); degradation of extracellular matrix proteins by matrix metalloproteinase (MMP); and migration of the endothelial cells mediated by membrane adhesion molecules, differentiation of the endothelial cells and formation of tube structures [Bussolino, F. et al., Trends. Biochem. Sci. 22:251-256, 1997; Kuwano, M. et al., Intern. Med. 40:565-572, 2001; Risau, W. Angiogenesis and endothelial cell function. Arzneimittelforschung 44:416-417, 1994].
Accordingly, the inhibition of the above steps has emerged as new therapeutic strategy for treating various angiogenesis-related diseases including cancers. Protease inhibitors, tyrosine kinase inhibitors, chemokines, interleukins and fragments of matrix proteins are developed as angiogenesis inhibitors [Abedi, H. et al., J. Biol. Chem. 272:15442-15451, 1997; Cao, Y., Int. J. Biochem. Cell Biol. 33:357-369, 2001; Fong, T. A. et al., Cancer Res. 59:99-106, 1999; Kwon, H. J. et al., Acalycigorgia inermis. J. Microbiol. Biotechnol. 11:656-662, 2001]. However, at present, few treatments are available which can effectively suppress angiogenesis and be used to treat angiogenesis-related diseases.
An immunosuppressant is a substance that performs immunosuppression of the immune system. They are mainly used to treat autoimmune diseases, and are largely classified into corticosteroid agents, cytotoxins, T cell signaling inhibitors, and the like.
When corticosteroids, which are steroid derivatives, bind to steroid receptors in the cytoplasm, and Hsp90 is dissociated from them, a complex of the drug and the receptor migrates into the nucleus, thereby exhibiting immunosuppressive effect. However, this drug is highly likely to remain in the body, and is reported to cause fatal results when administered for a long period of time, because it is highly likely to cause body weight increase, diabetes, loss of bone marrow, and adverse effects on reproductive function [Barnes P J, Clin. Sci. (Lond)., 94(6): 557-72. 1998; Boumpas D T et al., Ann Intern Med., 119(12): 1198-208, 1993]. Cytotoxins interrupt gene (DNA) synthesis in dividing cells, thereby interrupting clonal expansion of T cells and suppressing immune response. Typical examples of the cytotoxins include azathioprine and cyclophosphoamide. It is reported that they may damage other differentiating cells [Aarbakke J, Janka-Schaub G, Elion G B., Trends Pharmacol. Sci., 18(1): 3-7, 1997]. Further, they are known to induce severe adverse reactions, including reduced leucocytes and leukemia.
Accordingly, at present, T cell signaling inhibitors are hailed as immunosuppressants. The T cell signaling inhibitors exhibit immunosuppressive function by interrupting the signal pathway required for cell division. Cyclosporine A and FK506, which inhibit the production of interleukin-2 (IL-2) by interrupting the action of calcineurin, which is one of important molecules in immune response, are typical examples.
In the course of studying the physiological functions of the capsinoids capsiate and dihydrocapsiate, the inventors of the present invention found out that they function to suppress inflammatory response, angiogenesis and immune response and completed the present invention by developing a composition for preventing or treating inflammatory disease or angiogenesis-related disease or for inhibiting immune response comprising capsiate or dihydrocapsiate.